In living cells and organisms the activity of enzymes is first regulated by the novo synthesis and chemical modification of enzymes.
When fast adaptation of a cell or an organism to an altered environmental situation and simultaneously a higher activity of a specific enzyme is required, it does not mean that always a higher amount of this enzyme is synthesized de novo. Often, an already existing pool of enzymes is activated. For instance digestive enzymes (proteinases) are transferred from their storage form, the so-called zymogenes, to active proteinase. When necessary, blood coagulation factors are likewise transferred from the inactive storage form to the biologically active form.
Known activating mechanisms of storage enzymes are cleavage by specific peptidases, phosphorylation by proteinkinases, release from vesicles and the changing of the protein conformation by allosteric ligands.
An excess of activating reactions mentioned and the long-term effect of the activated enzymes is prevented by the controlled degradation or the specific inhibition of these enzymes. For example, the biological activity of activated proteinases is often blocked by specific proteinase inhibitors.
In the past few years the clinical and pathogenetic relevance of different proteinase inhibitors was recognized (1,2). It was found that lysosomal proteinase inhibitors are suitable for the therapy of sepsis, of chronic diseases of the rheumatic type as well as of diseases of the upper pulmonary system. At the moment, however, there are not proteinase inhibitors known that could be used in the treatment of these diseases. For the time being only the proteinase inhibitor aprotinin is used in therapy. Aprotinin is used for the treatment of postoperative haemorrhages caused by hyperfibrinolysis and the early treatment of shocks.
For the therapy of the above-mentioned diseases HUSI (Human-Seminalplasma Inhibitor)-type I inhibitors might be suitable. They are proteins. Examples for the group of HUSI-type I inhibitors are the proteinase inhibitors HUSI-I, CUSI-I (Cervix-Uterus-Secretion Inhibitor) and BSI (Bronchial-Secretion Inhibitor).
HUSI-I is an acid-resistant proteinase inhibitor from human seminal plasma and inhibitors proteinases from the lysosomal granula of the granulozytes, such as elastase. HUSI-I only exhibits a reduced inhibitory activity against other intracellular or extracellular proteinases. Its molecular weight is about 11,000. A partial amino acid sequence of HUSI-I was published by Fritz (48).
In addition to HUSI-I there exists a further acid-resistant proteinase inhibitor in the human seminal plasma, namely HUSI-II (3). Its molecular weight is about 6,500. HUSI-I and HUSI-II have completely different inhibitory spectra. While the inhibitory activity of HUSI-II is limited to trypsin and akrosin, the most remarkable property of HUSI-I is the specific inactivation of proteases from the lysosomal granula of the granulozytes, e.g. of elastase. Because of its different biological activity, HUSI-II is thus no HUSI-I inhibitor.
The acid-resistant inhibitor CUSI-I was isolated from the cervix-uterus secretion (4). The molecular weight of CUSI-I is almost identical with that of HUSI-I. Moreover, HUSI-I and CUSI-I have the same inhibition spectrum. In the Ouchterlony immuno-diffusion test HUSI-I and CUSI-I show immunological cross-reaction with anti-HUSI-I antibodies (5, 6). Finally, the amino acid analyses of HUSI-I and CUSI-I, so far only fragmentarily known, are almost identical (47).
The bronchial-secretion inhibitor (BSI) was isolated from the bronchial secretion (41, 44, 45, 46). The sequence of the first 25 amino acids of BSI was incompletely published in (41). BSI has a molecular weight of about 10,000. In immunological tests BSI shows a cross-reaction with rabbit anti-HUSI-I antibodies (47). BSI is acid-resistant and inhibits the proteinases leukozyte elastase, cathepsin G, trypsin and chymotrypsin.
Although the biological activity of HUSI-type I inhibitors was essentially known, so far these inhibitors could not be used for therapeutical purposes since they were not available in sufficient amounts in essentially pure form.